S272: SAFETY AND EFFICACY OF RM-001 IN PATIENTS WITH TRANSFUSION-DEPENDENT Β-THALASSEMIA: EARLY RESULTS FROM THE ONGOING OF AUTOLOGOUS HBG1/2 PROMOTER-MODIFIED CD34+ HEMATOPOIETIC STEM AND PROGENITOR CELLS
Authors: Rongrong Liu, LI Wang, Hui Xu, Xiaolin Yin, Junbin Liang, Wenqiang Xie, Gaohui Yang, Yaoyun LI, Yali Zhou, Lei Shi, Bin Xiao, Lingling Shi, Zeyan Shi, Xuemei Zhou, Jianpei Fang, Xiangmin Xu, Yongrong Lai, Junjiu Huang, Xinhua Zhang
Journal: HemaSphere (2023)

Background: Reactivating fetal globin (HbF) is a promising treatment for β-hemoglobinopathies. Using gene editing to mimic these mutations should reactivate γ-globin in patients with transfusion-dependent β-thalassemia (TDT) and ameliorate the symptoms of patients. RM-001 is a novel cell therapy that uses non-viral, ex vivo CRISPR-Cas9 gene editing in autologous hematopoietic stem and progenitor cells (HSPCs) at the promoter of the γ-globin genes (HBG1/2) to disrupt the binding site of BCL11. Aims: Here, we present available safety and efficacy results from all patients that received RM-001 infusion from two ongoing clinical trials (ChiCTR2100053406 & ChiCTR2100052858), including a recent treated TDT patient (β0/β0) who also carries two α-globin genes deletion (--/αα). Methods: Patients (6–35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF and plerixafor. CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the binding site of BCL11A on the HBG1/2 promoter. Prior to RM-001 product infusion (day 0), patients received myeloablative conditioning with Busulfan from day-7 to day-3. Patients were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, HbF and F-cell expression, and pRBC transfusion requirements. Bone marrow cells were obtained at 3, 6, 12 and 24 months after RM-001 infusion to measure the on-target allelic editing frequency using next-generation sequencing. Results: Data presented here for all 6 TDT patients have been treated with RM-001. As of February 28, 2023, patients were followed up for 2 to 15 months and 5 of them have been followed up more than 12 months. Five patients have β0/β0 genotype (CD17/CD41-42, n=1; CD41-42/CD41-42, n=4) and the other has β0/β+ genotype (CD41-42/IVS-II-654). In addition to β-thalassemia (CD41-42/CD41-42), the sixth patient (25yo) also carries two α-globin genes deletion (--SEA/αα). Patients had received a mean of 56.2 units/y pRBC transfusions (range: 39-79.6 units/y). All patients received a single dose of RM-001 cells, and achieved both neutrophil and platelet engraftments 2 to 3 weeks after RM-001 infusion (neutrophil: day 13-19, platelet: day 10-22). All patients ceased pRBC transfusions within 1 month after RM-001 infusion and achieved transfusion-independent (TI, total Hb continued ≥ 9g/dL) within 2 months (Figure). At 4 month post-RM-001 infusion, HbF reached 10g/dL in the first 5 patients and continuously maintained over this level through the reported period. At 2 month post-RM-001 infusion, the sixth patient had a total Hb of 11.7g/dL with 78.0% of HbF. The safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. No RM-001 related SAE report. Summary/Conclusion: The updated data reported here from 6 patients with TDT infused with RM-001 demonstrated clinically meaningful increases in total hemoglobin (Hb) and HbF levels. All patients stopped receiving pRBC transfusions within 1 month after RM-001 infusion and remained transfusion-free through the time of this analysis. The safety profile of RM-001 is generally consistent with myeloablative conditioning and autologous hematopoietic stem cell transplantation. These results strongly support continued investigation of RM-001 as a potential cure for patients with TDT. Submitted on behalf of the RM-001 Investigators.Keywords: Gene therapy, Thalassemia, Autologous hematopoietic stem cell transplantation